Recently the phosphodiesterase 4D (PDE4D) gene has been identified as a risk factor for ischemic stroke (Gretarsdottir, et al., Am J Hum Genet (2002) 70:593-603). Gretarsdottir et al. (2002) conducted a whole genome scan and found a linkage peak (LOD=4.4) on chromosome 5q121. Fine-mapping and association studies identified PDE4D as the gene linked to ischemic stroke in an Icelandic population (Gretarsdottir, et al., Nat Genet (2003) 35:131-138). Furthermore, mRNA levels of several PDE4D isoforms in transformed B-lymphocytes varied significantly between stroke cases and controls (Gretarsdottir, et al., (2003), supra).
PDE4D is a large gene that spans 1.5 Mb and has at least 22 exons and eight splice variants (Gretarsdottir, et al., (2003), supra; Wang, et al., Cell Signal (2003) 15:883-891; and Bolger, et al, Biochem J (1997) 328:539-548). PDE4D hydrolyzes cyclic AMP (cAMP) (Conti, et al., J Biol Chem (2003) 278:5493-5496) and is expressed in multiple tissues with varying expression patterns of the splice variants (Wang, et al., supra). PDE4D is found in brain, lung, kidney, macrophages, monocytes, B- and T-lymphocytes, and vascular smooth muscle cells (Bolger, et al., supra; Conti, et al., supra; and Pan, et al, Biochem Pharmacol (1994) 48:827-835). Several studies have reported PDE4D involvement in inflammation, proliferation, and migration, processes implicated in stroke occurrence (Ariga, et al., J Immunol (2004) 173:7531-7538; Miro, et al, Biochem Biophys Res Commun (2000) 274:415-421; Palmer, et al., Circ Res (1998) 82:852-861; Pan, et al, supra; and Johnson-Mills, et al., Biochem Pharmacol (1998) 56:1065-1073).
The association of specific PDE4D SNPs and haplotypes with stroke was initially identified in an Icelandic population (Gretarsdottir, et al., (2003), supra). However, until the present invention, the associations of specific PDE4D SNPs and microsatellites with stroke in specific subpopulations have not been evaluated. The present application addresses this need.